Chemotherapeutic agents of the sulphonamide type



Patented Sept. 10, 1946 CHEMOTHERAPEUTIC AGENTS OF THE SULPHONAMJDE TYPE William A. Lott, Maplewood, Frank H. Bergeim, Highland Park, and Kathryn A. Losee, New Brunswick, N. J., assignors to E. R. Squibb & Sons, New York, N. Y., a corporation of New York No Drawing. Application February 4, 1942, Serial No. 429,578

Claims. (01. 260'397.7)

This invention relates to, and has for its object the provision of: (A) (Amino-benzene-sulphonamido) -aminophenol ethers; (B) salt-type derivatives thereof; (C) intermediates formed in the preparation of (A) and (D) methods of preparing (A), (B) and (C). Compounds (A) and (B) are valuable chemotherapeutic agents, being especially promising as antimalarials.

The invention comprises especially: (A) compounds of the general formula wherein R, R', R R and R represent each a member of the group consisting of hydrogen, hydrocarbon (preferably lower alkyl), substituted hydrocarbon (preferably dialkylaminoalkyl) and acyl (including sulphonyl) radicals, and R represents a member of the group consisting of hydrocarbon (preferably lower alkyl) and substituted hydrocarbon (preferably dialkylaminoalkyl) radicals; (B) salt-type derivatives of (A); (C) intermediates formed in the preparation of (A); and (D) methods of preparing (A), (B) and (C).

The method of preparing the compounds of this invenion essentially comprises condensing a compound of the group consisting of nitro-aminophenol ethers, alkylamino-amino-phenol ethers, and acylamino-amino-phenol ethers with a member of the group consisting of nitro-benzene-sulphonyl halides, alkylamino-benzene-sulphonyl halides, and acylamino-benzene sulphonyl halides. When the compounds are prepared from the nitro-amino-phenol ethers and/or the nitrobenzene-sulphonyl halide reactants, there are produced intermediate nitro compounds of the general formula to the corresponding amino compounds by reduc- 7 tion or catalytic-hydrogenation. When the compounds are prepared from the acylamino-aminophenol ether and/or acylamino-benzene-sulphonyl halide reactants, acylamino compounds are obtained, which may be converted into the corresponding amino compounds by hydrolysis. The (amino-benzene-sulphonamido) aminophenol ethers are generally amphoteric compounds, forming acid-addition salts with hydrochloric, sulphuric, boric, nitric, lactici, tartaric, and other acids commonly used to solubilize amine bases, as well as salts with bases, for example the alkali-metal bases and organic-amine bases. Some of the salts, it should be noted, are insoluble or only slightly soluble in water.

Compounds (B) also comprise salt-type derivatives in which R and/or R represent salified groups such as the following:

(I)-CO(CI-Iz)nCOO-(alkali metal( wherein n is an integer from 2 to 5 (11) (lower alkyl) SOs--(alkali metal) (III) -'-alkyleneSO2-(alkali metal) Thus, compounds embodying group (I) may be obtained by reacting the (amino-benzene-sulphonamido) -aminophenol ether with the appropriate aliphatic dicarboxylic acid anhydride (especially succinic anhydride), and converting the resulting acid (e, g., succinamic acid) into the corresponding alkali metal including ammonium-salt; compounds embodying group (II) may be obtained by adding the (amino-benzenesulphonamido)-aminophenol ether to a solution of sodium bisulphite and a lower aliphatic aldehyde, heating the mixture until a clear solution is obtained, isolating the crude product by evaporating the solution to dryness, and purifying the crude product, e. g., by recrystallization from diluted alcohol; and compounds embodying group (III) may be obtained by reacting the (amino-benzene sulphonamido) aminophenol ether with an alkali-metal aldehyde-sulphoxylate (e. g., sodium formaldehyde sulfoxylate) in a suitable solvent (e. g., glacial acetic acid). If the (amino-benzene sulphonamido) aminophenol ether has both amino groups available, compounds in which both R and R. represent such salified groups are obtained. To obtain a compound in which R. alone represents such a group, an (amino-benzene sulphonamido) nitrophenol ether is used as the reactant, and the resulting nitro salt-type derivative is then catalytically-hydrogenated to the corresponding amino salt-type derivative; and to obtain a compound in which R alone represents such a group, a (nitro-benzenesulphonamido) -aminophenol ether is used as the 3 reactant, and the resulting nitro salt-type derivative is then catalytically-hydrogenated to the corresponding amino salt-type derivative.

The following examples are illustrative of the invention:

EXAMPLE 1 (a) PREPARATION or 2-(P-ACETAMINO-BENZENE- SULPHONAMIDO) -5-NITR0-ANIS0LE (b) PREPARATION or Z-(P-AMINO-BENZENE- SULPHONAMIDO-5-NI1R0-ANISOLE 50 g. crude 2 (p-acetamino-benzene-sulphonamido) -5-nitroanisole is added to a mixture of 500 cc. alcohol and 500 cc. hydrochloric acid, and the mixture is refluxed until a clear solution is formed and for one hour thereafter. On removal of the alcohol (by distillation) and cooling, a crystalline precipitate forms, and is filtered oif and washed several times with alcohol. The product, 2 (p-am-ino-benzene-sulphonarnido) -5-nitro-anisole, melts at 173-4" C.

(c) PREPARATION or Z-(P-AMINO-BENZENE- SULPHONAMIDO).-5AMINO-ANISOLE Procedure I g. 2-(p-amino-benzene--sulphonamido)-5- nitro-anisole is suspended in 225 cc. aqueous acetic acid, and treated with hydrogen under atmospheric pressure in the presence of Adams platinum catalyst, until approximately 4,630 cc. hydrogen has been absorbed. The catalyst is removed from the reaction mixture by filtration; and the filtrate is concentrated under reduced pressure to give a solid, which is dissolved in dilute aqueous hydrochloric acid. The solution is treated with decolorizing carbon and filtered, and the free base is precipitated by adding dilute sodium hydroxide; and the product is further purified by dissolving it in excess dilute sodium hydroxide, filtering, and adding dilute hydrochloric acid until no further precipitation occurs. On recrystallization from aqueous alcohol, the product, .Z-(p-amino-benzenesulphonamido)-5-amino-anisole, melts at 181-2" C.

Procedure II 20 g. 2-(p-amino-benzene-sulphonamido)-5- nitro-anisole and 20 g. powdered iron are mixed in a mortar; and 80 cc. acetic acid is then heated to about 70 C., and the mixture is added thereto in small portions so that a mild ebullition continues throughout the reaction. Sufficient water is added to hydrolyz the acetate and precipitate the amine base, and the liquid is removed from the solid by centrifugation. The solid, containing the product and excess iron, is extracted twice with 10% sodium hydroxide; and the centrifuged supernatant is filtered and made just alkaline to Congored. The precipitate is filtered, and recrystallized from alcohol; the thus-obtained Z-(p-amino-benzene-sulphonamido)-5-amino-anisole melts at 186-8 C. (uncorrected) (d) PREPARATION or Z-(P-AMINO-BENZENE-SUL- PHONAMIDO) 5 AMINO ANIsoLE HYDROCHLO- RIDE The 2 (pamino-benzene-sulphonamido) -5- amino-anisole is dissolved in absolute alcohol, an equivalent quantity of diy hydrochloric acid is added thereto, and the salt is precipitated by adding ether (or by evaporating the alcoholic solution to dryness). An aqueous solution of the hydrochloride may b prepared without isolating the salt by adding the 2-(p-amino-benzene-sulphonamido)-5-amino-anisole to the requisite quantity of a dilute aqueous solution of hydrochloric acid.

(2) PREPARATION or THE SODIUM SALT or 2-(P- AMINO BENZENE SULPHONAMIDO 5 AMINO- ANISOLE The 2 (p-amino-benzene-sulphonamido.) -5- amino-anisole is suspended in boiling alcohol, and a moderate excess (over the equivalent quantity) of alcoholic sodium hydroxide is added. The solution is then evaporated to dryness in vacuo to give the sodium salt of Z-(p-aminobenzene sulphonamido)-5-amino-anisole. An aqueous solution of the sodium salt may be prepared Without isolating the salt by adding the 2- (p amino benzene-sulphonamido) -5-aminoanisole to the requisite quantity of a dilute aqueous solution of sodium hydroxide.

(f) PREPARATION on THE DI- (SODIUM FoRMALnE- HYDE SULPHOXYLATE) DERIVATIVE or 2-(P- AMINO BENZENE SULPHONAMIDO) 5 AMINO- ANIsoLE A mixture of 8.8 g. z-(p-amino-benzene-sulphonamido)-5-amino-anisole and 11 g. sodium formaldehyde sulphoxylate is added with stirring to 15 cc. glacial acetic acid. When a clear solution is obtained, ether is added until a solid precipitate forms. The precipitate is filtered off, washed with ether, and dissolved in a small amount of water, and the solution is neutralized with sodium bicarbonate on addition of alcohol and cooling, the inorganic salts precipitate out and are removed by filtration. Ether is then added to the filtrate, and th crystalline precipitate formed is filtered off, washed, dried, and purified by recrystallizing from 50% alcohol. The product is a derivative of 2-(p-amino-benzene sulphonarnido) -5-amino-anisole in which both R and R are methane sodium sulphinate groups.

(a) PREPARATION or THE MONO-(SODIUM FORM- ALDEHYDE SULPHOXYLATE) DERIVATIVE OF 2-(P- AMINO BENZENE SULPHONAMIDO) 5 AMINO- ANISOLE A mixture of 9.7 g. 2-(p-amino-benzene-sulphonamido) -5-nitro-anisole and 5.5 g. of sodium formaldehyde sulphoxylate is added with stirring to 15 cc. glacial acetic acid. When a clear solution is obtained, ether is added until a solid precipitate forms. The precipitate is filtered off, washed with ether, and dissolved in a small amount of water, and the solution is neutralized with sodium bicarbonate; on addition of alcohol and cooling, the inorganic salts precipitate out and are removed by filtration. Ether is then added to the filtrate, and the crystalline precipitate formed is filtered off, washed, dried, and

purified by recrystallizing from 50% alcohol,

This nitro compound is then dissolved in alcohol (uncorrected).

and hydrogenated, using Adams platinum oxide catalyst. The product is a derivative of 2-(pamino benzene-sul'phonamido)-5-amino-aniso1e in which R is a methane sodium sulphinate group.

' EXAMPLE2 (a) P EPARATION OF 2- (P-AClilTAMINO-BENZENE- SULPHONAMIDO) -4NITRO-ANISOLE 56 g. e-nitro-z-amino-anisole and 78 g. pacetamino benzene sulphonyl chloride are ground together in a. mortar, and'40 cc. pyridine is-added; and the dark-brown solution formed,

which soon becomes very viscous, is heated on a steam bath for an hour, and several volumes of cold water is added with stirring. The gummy precipitate formed, which later becomes granular, is' filtered off and washed with hot water; the product, crude 2 (p-acetamino-benzene-sulphonamido)-4-nitro-anisole, melting at 254-8 C. without further purification.

(b) PREPARATION or Z-(P-AMINO-BENZENE- V SULPHONAMIDO) -4-NITR0 -ANISOLE '70 g. of the crude 2-(p-acetamino-benzenesulphonamido) -4-nitro-anisole is added to a mixture of 700 cc. alcohol and 700 cc. 10% hydrochloric acid, and the mixture is refluxed until a clear solution is formed and for one hour thereafter. On removal of the alcohol (by distillation) and cooling, the hydrochloride of 2-(p-aminobenzene-sulfonamido) l-nitro-anisole separates, and is filtered off. The free base, obtained by suspending the hydrochloride in water and adding an equivalent quantity of dilute sodium hydroxide solution, melts at 188-190 C.

(c) PREPARATION or 2-(P-AMINo-BENzENE-;

SULPHONAMIDO) -4AMINO-ANISOLE- .10 g. 2-(p-amino-benzene-sulphonamido) -4- nitro-anisole and 10 g. powdered iron are thoroughly mixed in a mortar; 40 cc. acetic acid is then heated to about 70 C., and while agitating the acetic acid in a flask, the mixture is added thereto in small portions at such rate that a mild ebullition continues throughout the reaction. The reaction mixture is then cooled, sufficient water is added to hydrolyze the acetate and precipitate the amine base, and the liquid is removed from the solid portion by centrifugation. 300 cc. 10% sodium-hydroxide solution is added to the (Fisher melting-point block), may be used.

solid, and the mixture stirred thoroughly and centrifuged; and the solid is again extracted with 10% sodium hydroxide solution and centrifuged. On filtering the supernatant and making it just alkaline to Congo red, the product, Z-(p-aminobenzene-sulphonamido) -4-amino anisole, precipitates as a light tan powder. After recrystallization from 50% alcohol, it melts at 231-3 C.

(d) PREPARATION or THE DI-(ACETALDEHYDE-SO- rnnvr BISULPHITE) DERIVATIVE or 2-(P-AMINQ- BENZENE-SULPHONAMIDO) -4-AMmo-AmsoI.r:

' To a saturated solution of 3.5 g. sodium bisulphite 1116 cc. cold water is added 1.8 cc. acetaldehyde', and'the mixture is stirred for-about one hour. Then 5 g. 2 (p-amino-benzene-sulphonamido) -4-amino-anisole is added to this solution, and the mixture is heated on the steam bath for about one hour, at the end of which time there is a"'clear solution. The solution is evaporated to dryness, and the product is recrystallized from 95% alcohol. The product is a derivative of 6 2 -(p-amino-benzene sulphonamido) 4 aminoanisole in which both R and R are u-ethane sodium sulfonate groups. (e) PREPARATION or 'I'HE Morro-(Acnrarnsnvnn- SODIUM BISULPHITE) DERIVATIVE or 2- (P-AMINO- .BENZENE-SULPHONAMIDO) -4AMINO-ANISOLE To a saturated solution of 16.9 g. sodium bisulphite in 25 cc. water is added 7.1 g. acetaldehyde,

.and the mixture is stirred for about one hour.

detailed in (d), (e), (f), and (g) of Example 1.

EXAMPLE 3 (a) PREPARATION OF 3-NITRO 4 (P-ACETAMINO- BENZENE-SULPHONAMIDO) -ANISOLE Procedure I 168 g. 3-nitro-4-amino-anisole is intimately mixed with 233.5 g. p-acetamino-benzene-sul- .phonyl chloride, and the mixture is treated with cc. pyridine. On additionof water to the resulting dark solution, 3-nitro-4-(p-acetaminobenzene-sulphonamido) -anisole is precipitated as a granular material. The product is purified by dissolving it in dilute aqueous alkali, reprecipitating it by acidifying the solution, and recrystallizing from 50% alcohol, and then melts at 173-4 C. (uncorrected). Y

Procedure II 168 g. B-nitro-l-amino-anisole is dissolved in 336 cc. pyridine, using alittle heat if necessary. Solid p-acetamino-benzene-sul-phonyl chloride is then stirred into this solution gradually, not allowing the temperature to rise above 50 C. After standing a few hours at room temperature, the

solution is diluted with water, and made acid to 7 Congo red with hydrochloric acid. The product precipitates as a yellow-orange crystalline prod- Y uct, and on recrystallizing from alcohol, melts at (b) PREPARATION or 3-NITRO-4-(P-AMINO-BEN- ZENE-SULPHONAMIDO) -.ANISOLE 175 g. 3-nitro-4-(p-acetamino-benzene-sulphonamido) -anisole is digested for an hour with 3500 cc. of a 1:1 mixture of 10% aqueous hydrochloric acid and alcohol, the compound gradually going into solution; and the solution is then cooled, and adjusted to a pH of about 5-6 by the addition of 40% sodium hydroxide solution. The thus-precipitated yellow granular substance, 3-nitro 4 -(p amino benzene-sulphonamido) anisole, after purification by recrystallization from alcohol, melts at 118-9 C.

(c) PREPARATION OF 3-AMINO-4-(P-AMINO-BEN-L ZENE-SULPHONAMIDO) ANISOLE Procedure I 30 g. 3- nitro-4-(p-amino-benzene-sulphonami do) -anisole is added gradually to a hot suspension The product is a derivative of 2-(p-v filtrate-by adding dilute .sodium hydroxide; The 150 precipitate; a pi-nkish-crystalline material; is re crystallized from'n butanol togive the B amino- 4- (p-amino-benzene sulphonamido) anisole as anialinost pure, white crystalline-anaterial melt Procedure II g. 3-'nitro=4;-(p amino=benzene'-sulphonamidor-anisole and 10. g: powderediron' are mixed in an mortar; cc: acetic acid isthenheate'dto';

70 0., and the mixture added thereto in" small amounts just fast enough .t'ocause mild ebullition throughout the reaction. Sufilcient water isthen. added to. the... cooled. reaction. mixture, to hydrolyze the acetate and precipitate the amine base, and the liquid is removed by centrifuging. Thelsolid portion is-ex-tracted twice with 10% sodium hydroxide, centrifuged and-.the supernatant .liquid. filtered; and. the: filtrate is madejust acid to: Congo r.ed..v The-precipitate, 3.-amino-4.- (p;aminosbenzene=sulphonamido). -anisole,. after recrystallization from 50%; alcohol, melts at 194+5-9 C. (uncorrected);

Procedure. III

5 g; 3-nitro-4-(p-acetamino-benzene-sulphonw mido)-anisole (cf. Example-31m) and-5 g; pow dered iron are mixe'd ina" mortar; 10 cc. acetic acidis then heated to about 70 C., andthe mixture isadded theretoin small portions just fast. enough tocause a mildebullition throughoutthe: reaction. Theflmixture is cooled, andtsufilcient" water isadded tov hydrolyze the acetate and precipitate the amine base, and the liquid isremoved'by centrifuging. The. soli'dportion' is;extracted twice with 10%, sodium hydroxide; and. the extract is centrifuged and the supernatant filtered and" made just alkaline to Congo red. The product, 3 aminol-(p-acetamino-benzene= sulphonamido)-anisole, after recrystallization from alcohol, melts a-t11"7l-3"C. (uncorrected) The 3amino-4= (p acetamino -benzene sulphonamido).-anisole.. is. then converted into..- 3- amino=4-. (p-aminosbenzenersulphonamidmranir 6O sole. by.hydrolysis with.1.0 aqueous :hydro chloric. acidas detailed inExampleB .(b)...

The 3'-amino.-4-.(praminorbenzene-sulphonae mido).-anisole, may. be. converted into. various. saltet'ype derivativesby the, proceduresldetailedl. in (6), (hand (9) ofv Example 1; andinidl and. (e). of..Examp.le.2..

0 (a) PRneARAnom or" as (P-ACETAMINO'PBENZENE'T 7 SULPHONAMIDO'XL- 4LACETAMINO1-ANISOLE 30 g. 3-nitro-4-acetamino+anisole is suspended in 600 cc. alcohol and hydrogenated, using Adams platinum oxide. catalystl The catalystisfiltered. 75,

The residue, crude 3-amino 10.

ofi;l andrthezfiltrate; concentrated Jinavacuum .at; 40? G3; after crystallization from; absolute alcohoh. the:product; 3samino+4eacetaminosanisole; melts;

13 g. p-acetamino-benzene-sulphony1 chloride;

is added slowly, witlir.coolirig;' tb 13 cc. pyridine,

andthesolutionis,.added slowly, with cooling to.

a suspensionlof; 10' g....3 aniinoAeacetamino-ani sole in 15"cc. pyridine. The deep red liquid formed is allowed to stand ior an hour; and cold water is' add'ed thereto; and the redgranular-pre' cipitatezformedis filteredoff, washed with water; and recrysta'llized from"5'0 alcohol.

acet'amihmanisole; melts at 230-1 C; rected);

(b PREPARATION- on 3.-(AMINO.-BENZENE-:SUL.= PHONAMIDO.) -4rAMINO-ANISOLE.

20 g: 3- (p acetamino-benzene-sulphonamido)--- d' acetamino-anisole; 200- cc; 10%- hydrochloric acid, and 20 cc. alcohol (to prevent foamingY-are boiledfor an hour; and the clearsolutioniormed is filtered; cooled; and made just allialineto Congo red by the addition of 10% sodium hydroxide, a lightecoloredvx precipitate being formed. The

precipitate, 3 (p-amino-benzene-sulph'onamido) 4-aminoanisole,- is filtered off, and after recrystallizationfrom 50% alcohol,-melts at 178-9" C. (uncorrected) EXAMPLE 5.

(a) PREPARATION OF 3- (P=NITRor-BENzENE SUL'-- PHONAMIDO) -4'-AcETAMINo'-AmsoLE;i

15.2, g, vp-nitrorhenzenersulphonyl. chloride is slowly addedtov, 15 cc. pyridine, While'cooli'ng,

and the solution is slowly addedto a suspension of 15; g;.; 3ramino-4aacetamino-anisole;in. 20 cc. pyridine; while ;c01ing The" deep-orange reaction mixture is allowed to stand for an hour, and cold water'is added thereto, a'granular orange precipitate being formed. The-precipitatey 3 (p-nitro-benzene-sulphonamido) 4 acetamino anisole, is filtered ofiand washed'with water;

andafter recrystallization-from alcohol, it melts at 183-5 C. (uncorrected).

(b) PREPARATION on 33-(P-AMINQ-BENZENE-,-SUL.- PHONA'MIDO)l-ACETAMINOe-ANISOLE 12.5 g. 3-'(p-nitrorbenzenersulphonamido),-4+ acetamino-anisole. in. 250' cc.. alcohol. is hydro-- genated in the .presence of Adams? platinum oxide catalyst. The. catalyst is. filtered off and the .fil-L trate concentrated. in. vacuo; the residue, 3-6pamino benzene. sulphonamido) 4- acetaminoanis0le,. after recrystallization. from. alcohol,.

meltsuat. -7 C. .(uncorrected)...

PREPARATION OF 2-AMINO-4-(PAMINO=BENZENE* SULPHoNAM1no).-ANIsoLE.

2"'-acetamino-4 -nitro=anisole'- is hydrogenated in alcohol" in the presenceof" Adams-- platinum oxide. catalyst. Thev catalyst is filtered ofi, and

the filtrate concentratedin vacuo. The product,.

2-acetamino+4amin0eanis0le,. after recrystalliization. from ,alcohol, melts. at. 107-8 C. (uncor rected).,

The 2-acetamino-4-aminoranisole., is con:

densed with p-acetarninmbenzenesulphonyl chloride-e. g. in themanner. describedin Example 4 (ab-and the, resulting 2-acetamin0,-4=:-

(p acetamino benzenesulphonamido) am:-

The pr0d--- uct; 3'-(p-acetamino benzene sulphonamido 4 (uncor product sole" (M. P. 242-4 0.) is hydrolyzede. g. in the manner described in Example 4(b)-to obtain 2 amino 4 (p amino benzene sulphona mido) -anisole (M. P. 1723 C.).

EXAMPLE 7 PREPARATION OF 2-AcE'rA1vrINo-4-(P-AMINO-BEN- ZENE-SULPHONAMIDO) -,ANISOLE EXAMPLE 8 PREPARATION or 3-NITRO 4 (P-ACETAMINO- I BENZENE-SULPHONAMIDO) -PHENETOLE 100 g. 3-nitro-4-amino-phenetole and 128.4 g. .p-acetamino benzene sulphonyl chloride are mixed in a mortar, and 66 cc. pyridine is added thereto A dark-red liquid is formed, with evolution of heat, The reaction mixture is heated onthesteam bath for a half hour, and cold water is added thereto; and the granular orange formed, 3-nitro-4-(p-acetaminO-benzene-sulphonamido) -phenetole, is filtered OE and washed with water. On recrystallization from alcohol it melts at 154-5 C. (uncorrected) .(b) PREPARATION or 3-NrrRo 4 (P-AMINO-BEN- ZENE-SULPHONAMIDO) -PHENETOLE precipitating the 3-nitro-4-(p-amino-benzene-' sulphonamidm-phenetole as an orange powder, which is then recrystallized from alcohol (M. P. 114-6 C.). r

(c) PREP RATION OF 3-AMINo-4-(P AMINo-BEN- ZENE-SULPHONAMIDO) -PHENETOLE g. 3-nitro-4-(p-amino-benzene sulphonamido) -phenetole and '10 g. powdered ironare mixed in a mortar; then. 40 cc. acetic acid is heated to about 70 C., and the mixture added thereto in small portions just fast enough to .cause'mild ebullition throughout the reaction.

Sufiicient Water is then added tohydrolyze the acetate and precipitate the'amine base, and the liquid portion centrifuged Off. The solid portion is extracted twice with 10% sodium hydroxide solution, and the supernatant obtainedby centrifuging is filtered and made I just alkaline 'tO Congo red. The precipitate, 3-amino-4-(pamino benzene-sulphonamido)-phenetole, is recrystallized from 50% alcohol (M. P. 241-2 0.).

EXAMPLE 9 PREPARATION or 3.- (ErnYL-SuLrHoNANIIno) -4- (P- AMINO-BE' zENEj-SULPHoNAr/uno) -ANIsoLE 33.5 g. of 3-amiriO-4(p-acetamino-benzene sulphonamido)-anisole (of: Example 3'(e)' Proceup with water until it granulates.

- chloride.

water.

I cohol.

.under reduced pressure. in benzene, 'washed several times with dilute so- 10 dure- III) is mixed with 16g. pyridine, andthen gradually treated with 13 g. ethyl-sulphonyl ture is diluted with 300 cc. ice water, and the gummy precipitate which first forms and soon becomes granular is filtered off and Washed with The product,. S-(ethyl-sulphonamido) 4(p-acetamino-benzene-sulphonamido) anisole, is then digested for one hour with 300 cc. 10% aqueous hydrochloric acid, whereupon it graduallyenters solution therein. After cooling and filtering off a small amount of undissolved material, the solution is neutralized to about pH 6 by the addition'of 10% aqueous sodium hydroxide. The resulting granular precipitate, 3-(ethy1-su1- phonamido) -4-(p amino benzene sulphona mido)-'anisole, isobtainedas a white crystalline material by recrystallization from 50% alcohol.

v EXAMPLE 10 PREPARATION OF 3-(P-AMINo-BENzENE-SuLPHoN- AMIDO) -4-DIMETHYLAMINO-ANISOLE 3-nitro-4 dimethylamino-anisole is hydrogen- 'ated in alcohol in the presence of Adams platinum oxide catalyst to Obtain 3-amino-4-dimethylamino-anisole. v

18 g, 3-amino-4 dimethylam'inoanisole is mixed with 24 g. p-acetamino-benzene-sulphonyl chloride, and then treated with 12 g. pyridine. A thick solution forms, which soon becomes warm and viscous. .After an hour, this solution is treated with 250 cc. water; and the gummy precipitate of 3-(p-acetamino-benzene-sulphonamido) -4-dimethylamino-anisole formed is rubbed After thoroughly washing with water, 25 g. of the acetylated compound ishydrolyzed by digesting with 250 cc. 10% hydrochloric acid for an hour. After cooling and filtering off any undissolved material, the solution is neutralized to a pH of'about 6 bym'eans of adueous sodium hydroxide solution;

the product, 3-(p-amino benzene sulphona- "mido)4 dimethylamino anisole separates as .a

granular solid, and is obtained practically white and crystalline by recrystallization from 50% al- PHONYL) N (,6 DIETHYLAMINO ETHYL) 4- AMrNo-ANIs LE 30 g. 3-nitro-4-(p-tolyl sulphonanflido) -anisole is dissolved in 113 cc. absolute alcoho1 by heating to boiling, and 15.5 g. fl-diethylamino-ethyl chloride hydrochloride is added thereto, followed by 27 .5 g. anhydrous potassium carbonate. The mixture is then refluxed for several hours and filtered hot; and the filtrate is concentrated to a syrup The syrup is taken up dium hydroin'de, then with water, and dried; and on distilling off the benzene, the 3-nitro-N-(ptolyl-sulphonyl) -N- (,B-diethylamino ethyl) -4- amino-anisole is left as an amber syrup.

(b) PREPARATION or 3-NI'rRo-4- (B-4DIETHYLAMINO- ETHY AMINO) -ANISOLE 10 g. 3 nitro-N- (p tolyl-sulphonyl) -N- (pi-diethylamino-ethyl) -4-amino-anisole is mixed with chopped ice, and strongly alkalinized'; and the After standing for an hour, the mix- 11 liberated .base is :taken up .in :benzene, and the solution .i idried and distilled under; reduced" pressure. The product, '3enitroe4-(pediethylaminosethylamino) -aniso1e,':is obtained asia'red oil boilito 'crystalsmeltingrat about :36-9 C.

.This base mayberconverted.tozits mono-hydrochloride by dissolving:in ether and'treating with the requisite quantitypffan ethereal solution of hydrogen chloride. iinz-alcohol and "precipitating .with ether, .it 1melts -at. 1-59+160 'C.

('c) "PREPARATION "QWB-AMINO- l-(p DIETHYL- .AMINO-JETHYLAMINO) -Ams0LE .5. ;-.-g. .-.-3-nitro-l-. cfi-diethylamino-ethyl). anisole .hydrochlorideii .dissolveddn -200 cc. of;95% .al-

cohol, and, .hydrogenated under slightly greater than atmospheric pressure using Adams platinum oxide catalyst. Whenthreeequivalents of hydrogen have been taken up, the catalyst is filtered off, and'the filtrate evaporated to removet'he "aqueous alcohol. 'The-residueisfiltereddff, and the filtrate evaporated .to :remove the aqueous alcohol, .and ...converted.to the .di-hydrochloride-of..3-,amino 4- .(cediethylaminoeethyl) .-aniso1e.by addin ethereal hydrochloric acid. After recrystallization fromabsoluteaalcohol the saltpartially melts at 160.'162 C.,.then resolidifies and decomposes .at 175 .0.

"(11) PREPARATION or *3 (-P-AMINo-BENzENE SuL- NO) -'AmsoLE ;3.1 ,g.'.'3.-amino-4-. (fl-Idiethylamino-ethylamino) aniscle'is mixed with23 g..p-.acetamino-benzenes1ilphonyl chloride, and the mixture is treated withflli .g. pyridine, .whereupon .the .mixture be- .comes hot.and forms athicksolution. Afteran 'hour,.abo1it l'3.00..cc...of water ..is added, and an acetyl derivative, .3- (p-acetaminobenzene sul- .phonamido) -(flediethylamino ethylamino) anisole, separates .as ,a pasty .soli'd. After thoroughly washing with water, this product is .hy- .drolyzed.bydigeSting for. about. an hour w-ith' 200 cc. 111% aqueoushydrochloric acidito .Whichabout 100 cc. alcohol has been added. The clear solution which forms is boiled, lastly with decolorizing carbon filtered, and. neutralized with aqueous sodium hydroxide to about pH '6, whereupon the product, '3-(p-amino-'benzene-sulphonamido) :4- (/3-diethylamino=ethylamino) =ariisole, separates as a granular solid; and on recrystallization from 50% .alcohol,the-product.ishbtained as a .buffi. colored -.crystalline solid.

EXAIVIPL'E 12 PREPARATION 1 OF 3- (IMAMINO-BENZENE*SULPHON- sm-n0) 4-CARBA-MIDO-ANISOLE 3-nitro-l-amino anisole is dissolved in glacial acetic acid and-an equivalent quantity of finelydivided "potassium cyanate is gradually added thereto. After-standing two "'da'yathe solid prod- 'uct,' 3 nitro-l=carbamido anisole, "is collected on afilter pad, washe'd with water;and catalyticallyhydrogenated in glacialacetic acid inthe'presence of .Adams..catalyst. When theltheoretical volume of hydrogenhaslbeen taken up,..the glacial acetic acid is removed in vacuo, the residue alkalinized with strong :saqueous =:so.dium Lhyclroxide, and rthe product taken :uprinether. r-After evaporationiof theeethenthe product, B-aminQ-A-carbamidQ-an- :isole is obtainedms 'a dark-colored semi-solid. eWithout ."purification, lt. is ta-ken up :in pyridine On=purification by dissolving 1 and alcohol.

::acetamino-benzeneqsulphonyl chloride. .iAfterca .rclear, dark-coloredssolution is:formed, it.'is.:a1- "lowed'to stand -1several hours,.and then diluted with water. The iproduct, 3-.(p-acetamino-benzene-sulphonamido) -4-.carbamido anisole, separates as a gummy precipitate. It is dissolved in dilute aqueous a-lkali,treated with decolorizing carbon, and reprecipitated by adding an excess of .dilutehydrochloric acid. The now granular precipitate, the acetyl derivative, is .filteredoff :and washed. .Itis then .hydrolyzed.by-.digesting forabout. an: hour withaqueous hydrochloric acid .andenough alcohol .to prevent .frothing. .The productis .then .isolatedas aigranular solidby neutralizin .to aboutpH 6 .with. aqueous sodium hydroxide.

EXANIPLE 13 PREPARATIGN or 3-PHENYLcARBAMIno-4- (P-AMINO- 'BENZENE SUIJPHQNAMIDO) JANISOLE 10% aqueous solution of the sodium salt of 3- 'aminol p-acetamino-benzene -'sulphonamido) :anisole is mixed with'an equivalent amount of phenyl isocyanate, "and shaken in the "shaking machine until the'odorof phenyl isocyanate has disappeared. 'Ihesolution'is-filtered to remove anydiphenyl'ureawhich'has formed, and'is then acidified; and theacetyl derivative, 3'-phenylcarbaniido-l- (p acetamino benzene-sulphonamido) anisole, separates as a granular powder. 'This powder is then digested for about an hour with a 50 mixture of 10 aqueous hydrochloricacid When-allthe acetylderivative has been hydrolyzed, a clear solutionresults, which is then cooled and neutralized to about pH 6 by the-addition of aqueous sodiumrhydroxide, whereuponthe product, 3-1,p'henylcarbamido 4 .(p- 'amino-benzeneesulphonamido) :anisole, separates :as a granular 1 powder.

Compounds embodying a substituted phenyl- -carbamido radical may the obtainedin the same manner, using the correspondingly?substituted phenyl 'isocyanate reactant.

.EXAMPLE l4 -(a) PREPARATION or 2,4?111-(9-A0ETAMIN0-BEN- =ZENE4SULPHONAMIDO) ANISOLE '25 g. ..2 ;4-.diamino-anisole dihydrochloride :and 27.5 g. p acetam'ino-benzene sulphonylchl'oride are mixed in a mortar, and 40 cc.' pyridine is added nthereto. .A .:deep:red liquid dorms and there is,a-.slight.rise:.intemperature. ,The reaction mixture is heated on the steam bath ,for one half hour, an'd 25 cc."50% sodium hydroxide Theoily gob which settles to with 10% hydrochloric acid, decanting after each washing. After standing 'for about one hour, the oil becomes granular, and is filtered. On'recrystallization'irom alcohol, the product, 2,4 di-'(peacetamino-benzene-sulphonamido)- -anisole, melts at 237 8" C. "(Fisher melting-point *block) C24l 2 C. (uncorrected).

.(b) -PRERARATION 032,4 .DI-(PvAMINOBENZENE- SULPHONAMIDO) wANISOLE '10- g. "2,4 di- (p-racetaminoebenzeneesulphonamide) anisole is hydrolyzed with about 1125 cc.

10% hydrochloric acid, a small amount of alcohol being added 'to prevent forming. A clear solution ,formsflafter heating about 40 minutes. The solution .is cooled, and .majdejjust alkaline to Congo red; and'the precipitate,"2,4-di'(p'-amino .benzene-sulphonamido) =anisole, .is :fi'ltered, wand :and treated ;with i the equivalent :quantity ..of ;px -recry'stal1ized..fr0m :alcohol.

base is extracted with ether, and added to 27.5 g.

p acetamino benzene sulphonylchloride suspended in 100 cc. ethyl acetate. The reaction mixture is allowed to: stand in the ice box for about three days, and the crystals formed are filtered off and dissolved in sodium hydroxide; and the solution is treated with activated charcoal and filtered. The filtrate is then made neutral with 10% hydrochloric acid. The pinkish precipitate formed, 2,5-di(p-acetaminobenzene-sulphonamido)anisole, is filtered off and recrystallized from alcohol; it melts at 176-9 C. (uncorrected).

(b) PREPARATION or 2,5 DI-(P-AMINO-BENZENE- SULPHONAMIDO) ANISOLE g. 2,5 di(pacetaminobenzene-sulphon amido) anisole is boiled for one hour with 200 cc. 10% hydrochloric acid. The clear formed is cooled, and made neutral to Congo red with sodium hydroxide. The precipitate, 2,5 di(p-amino-benzene-sulphonamido) anisole is filtered off and recrystallized from alcohol.

' .EXAMPLE 16 PREPARATION or 3,4-DI(P-AMINO-BENZENE-SUL- PHONAMIDO) ANISOLE (a) PREPARATION or 3-(P-ACE'1AMINO-BENZENE- SULPH NAMIDO) 4-BENZYLAMINO-ANISOLE g. 3- nitro-4f-amino-anisole is dissolved-by,

. warming in a'mixtur of 501cc. of benzyl alcohol and '10 cc. of benzyl chloride. The solution is heated under a reflux condenser for 12 hoursat about 100 C. on cooling, crude 3-nit'ro-4-benzylamino-anisole separates out in the form of red needles. It is purified by recrystallizingfrom aqueous alcohol, from which itsepalrates as bright red needles melting at 105C. i

19.5 g. 3nitroAbenzylamind-aniSole is dis solved in 225 cc. of absolute alcohol, and hydrogenated in the. presence of Adams platinum oxide catalyst. The solution changes from red to colorless or pale yellow. The catalyst is then filtered off, and the alcoholic filtrate is concentrated under reduced pressure to give crude 3- amino-4benzylamino-anisole as a red syrup.

17 3amino-4benzylamino-anisole is dissolved in 20 cc. pyridine, and 17.6 p-acetamino-benzenesulphony1 chloride is added thereto in small portions. The syrupy liquid is allowed to stand for solution about 24 hours at room temperature, after which 14 red. The product, 3 (p-acetamino-benzenesulphonamido) 4-benzylamino anisole separates out as a light-brown crystalline material, and is purified bycrystallizing from equeous alcohol.

(12) PREPARATION or 3-(P-AMINO-BENZENE-SUL- PHONAMIDO) 4-BENZYLAMIN0-ANI50LE 15.3 g. 3 (p acetamino-benzene-sulphon-.

amido) 4-benzylamino-anisole is added to 150 cc. 10% hydrochloric acid mixed with cc. of alcohol, and the mixture is refiuxed'until all the solid dissolves (about hour); It is then filtered hot, and the cooled filtrate is made alkaline to litmus with strong sodium hydroxide. The product, 3 (p amino-benzene-sulphonamido)4-benzylamino-anisole, separates out as a red gummy material, and is washed with water and crystallized from aqueous alcohol, and is then a pale-pink crystalline material.

Manifestly, a large number and variety of other (amino benzene sulphonamido) aminophenol ethers (A) and other compounds (B) and (C) may be obtained by the procedure of the foregoing examples, using the appropriate reactants. The following additional compounds, inter alia, are thus obtainable:

2 acetamino 5 (p nitro benzene sulphonamido) anisole 2 acetamino 5 (p amino benzene sulphonamido) anisole Z-acetamino 5 -(p-acetaminobenzene-sulphonamido) anisole 2-amino-5-(p-amino benzene sulphonamido) anisole 3-(2-nitro 4 methoxy phenyl carbamido)'-4- (ip-acetaminobenzene-sulphonamido) anisole [from 3-amino-4-(p-acetamino-benzene-sulphonamido)-anisole and 2-nitro-4-methoxyphenyl isocyanate] 3 (2 nitro4-methoxy-phenylcarbamido) 4-(paminobenzehe-sulphonamido) anisole 3- (2-amino-4-methoxy phenylcarbamido) -4(pamino-benzene-sulphonamido) anisole 3-(p-amino benzene sulphonamido) 5-aminoanisole I 3-acetamino 5 -(1p-acetaminobenzene-sulphonamido) anisole 3-amino-5-(p-amino benzene sulphonamido) 3- (p-amino benzene-sulphonamido) 4 (p-anisoyl-amino) anisole [from 3-nitro-4-aminoanisole and p-anisoyl chloride] I 3- (p-amino-benzenesulphonamido) 4- (p-nitrobenzoyl amino) anisole [from 3 nitro-4- amino-anisole and p-nitro-benzoyl chloride] 3 (p amino benzene sulphonamido) 4 (pamino-benzoyl-amino) anisole 3-diethylamino 4 (p amino-benzene-sulphon 1 amido) phenetole [from 3-diethylamino-4- amino-phenetole, obtainable by reacting 3- diethylamino-phenetole with phenyl-diazonium chloride, and reducing the resulting azo cornpound with SllClz and HCll' r r l 2 (c cliethylamino-ethylamino) 4 4' (p aminobenzene-sulphonamido) -anisole 2 (e diethylamino-ethylamino) 5 (p aminobenzene-sulphonamido) anisole 3 (p amino benzene-sulphonamido) 4- (lb-hydroxy-fichloro-iso-propylamino) anisole 3 (p-amino benzene-sulphonamido) 4-(p-hydroxy fidiethylamino-isopropylamino) anisole [by replacing the chloro radical in the immediately preceding compound with a diethylamino radical in the conventional manner] .anisole [by dissolving 3-amino-4(p-acetaminobenzene--sulphonamido) -anisole in a slight excess of aqueous alkali and boiling with c-diethylamino-ethyl chloride] A derivative of 3-amino--(p-amino-benzenesulphonamidm-anisole in which both R and R are methane sodium sulphinate radicals A derivative of 3-amino-4-(p-amino-benzenesulphonamido) -aniso1e in which R is a methane sodium sulphinate radical A derivative of 3-amino-4-(p-amino-benzenesulphonamido) -anisole in which R is a methane sodium sulphinate radical A derivative of 3-amino-4-(p-amino-benzenesulphonamido) anisole in which both R and R area-ethane sodium sulphonate radicals A derivative of B-aminol-(p-amino-benzenesulphonamido)aniso-le in which R is an m-ethane sodium sulphonate radical A derivative of 3-amino-4-(p amino-benzene su1phonamid0)-anisole in which R is an -a-ethane sodium sulphonate radical Manifestly, also, compounds wherein the amino group N RI and the sulphonyl group are meta or ortho to each other may be obtained by the procedure of the foregoing examples, using the appropriate meta or ortho nitro-benzene-sulphonyl halide, alkylamino-benzene-sulphonyl halide, or acylaminobenzene-sulphonyl halide; and compounds wherein either or both of the benzene rings contain further substituentswhich compounds it should be noted, are comprised by the genus (aminobenzene-sulphonamido)-aminopheno1 ethers may be obtained by using the correspondinglysubstituted nitro-amino-phenol ether, alkylamino-amino-phenol ether, or acylamino-aminophenol ether and/or the correspondingly-substituted nitro-benzene-sulphonyl halide, alkylamino-benzene-sulphonyl halide, or acylaminobenzene-sulphonyl halide in the procedure of the foregoing examples.

Among'other reactants utilizable in the procedure of the foregoing examples for the preparation of the compounds of this invention are:

pMethylamino-benzene-sulphonyl chloride p-Diethylamino-benzene-sulphonyl chloride 1'6 N -methy1-3-methoxy-o-phenylene-diamine 3-methoxy-N'-pheny1-p-phenyleneediamine 4-ethoxy-mephenylene-diamine 4-cyclohexyloxy-m-phenylene-diamine 4-phenoxy-o-phenylene diamine 2-ethoxy-p-phenylene-diamine z-butoxy-N -phenyl-p-phenylene-diamine 4-methy1-G-nitro-m-anisidine 6-methyl-2nitro-m-anisidine 6-methyl-5-nitro-m-anisidine 5-methyl-6-nitroo-anisidine 5-methoxy#m-phenylene-diamine 3-methoxy-o-phenylene-diamine 2-methoxy-p-phenylene-diamine 3-nitro-4-diethylamino-anisole (from '3-nitro-4- iodo-anisole and diethylamine) It is further obvious that (amino-benzenesulphonamido)-aminophenol ethers which contain one or more free amino groups may be converted into a variety of acyl derivatives other than those disclosed hereinbefore, inter alia, glycolic, thioglycolic, and malic acid derivatives. Thus, for example, 3-glycolyamino-4-(p-acetaminobenzene-sulphonamido) -anisole' may be obtained by fusing 3-amino-4-(p-acetamino-benzenesulphonamido)-anisole with an equivalent quantity of glycolic acid.

The invention is not to be construedas in any sense restricted to the foregoingspec'ific examples, compounds, reactants, procedures or steps, but may be variously otherwise embodied within the scope of the appended claims.

We claim:

1. A compound of the general formula wherein'R' represents a member of the group consisting, of hydrogen, hydrocarbon, dialkylamino-substituted-hydrocarbon, and acyl radicals.

2. A compound of the general formula NHzOSQENHOO-(iower alkyl wherein R represents a member of the group consisting of hydrogen, hydrocarbon, dialkylamino-substitutedhydrocarbon, and acyl radicals.

3. 3-amino-4- (p-amino-benzene sulphonamido) -aniso1e.

4. 3-amino-4-(p-aminoebenzene sulphonamido) -'phenetole.' i

5; 3-phenyl'carbamido-4 -(p amino benzenesulphonamido) -anisole. WILLIAM A. LOTT.

FRANK H. BERGEIM. KATHRYN A. LQS'EE. 

